Dry eye disease (DED) is a common condition that can cause discomfort and adversely affect visual quality and quality of life. Many subtypes of DED are associated with ocular surface inflammation. Inflammation of the ocular surface is mediated by both the innate and adaptive immune systems. Inflammation in DED can be associated with ocular pain. Mixed DED (MDE) is characterized by decreased tear production (aqueous deficient) and greater evaporation of the tear film (evaporative dry eye). MDE is often present in later stages of DED. DED amongst Veterans is common, and can be associated with a more severe symptom burden than civilians. Veterans are at risk for developing MDE due to high rates of multiple medication use and co-morbid conditions, like glaucoma, post-traumatic stress disorder and depression. Current treatment options are limited and primarily palliative. Great opportunity exists to improve the quality of life of Veterans by developing novel treatments for inflammation in DED. An area of the immune system that has been understudied and under-targeted by therapeutics in DED is the innate immune system. In particular Toll-like receptor (TLR) signaling pathways may be over-active in DED. Histatin is a family of peptides found primarily in saliva and is known to have significant wound healing and anti-bacterial properties. Little data exist on the mechanisms of action of histatin peptides. We have found that histatin peptides can improve the health of the ocular surface under experimental conditions that mimic DED. Our long term objective is to develop a new class of DED therapeutics that target the innate immune system to reduce ocular surface inflammation. Our central hypothesis is that histatin peptides can ameliorate the damaging effects of an overactive innate immune signaling in DED. We will utilize a well vetted model of MDE in order to show the efficacy of histatin peptides in treating DED. We will also undertake mechanistic studies to find the critical mediators of histatin peptide effects on innate immune pathways in ocular epithelia. The proposed research is innovative as it is the first study to investigate the use of histatin peptides as a treatment for innate immune over-activity in MDE. We believe the results of these studies will yield significant progress in the development of new therapeutics through the use of rigorous and well defined methods and metrics in clinically relevant translational models of disease.